Study identifies factors associated with mortality in HIV-positive people with cryptococcal meningitis

Rapid diagnosis and effective antifungal therapy are essential to reduce mortality rates in HIV-positive people with cryptococcal meningitis (CM), results of a study published in the online edition of Clinical Infectious Diseases show. The research also indicated that early antiretroviral therapy (ART) did not lead to immune reconstitution illnesses and would prevent deaths.

“This is the largest study examining factors determining outcome in HIV-associated CM,” comment the authors.  “Earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.”

Cryptococcal meningitis accounts for between 10 and 20% of HIV-related deaths in sub-Saharan Africa. It is normally associated with advanced immune suppression and the median time to death following admission to hospital is just 10 to 13 days. 

An international team of researchers wanted to establish a firm understanding of the factors associated with mortality so as to inform more effective treatment strategies.

They therefore pooled the results of nine trials conducted between 2002 and 2010 involving HIV-positive people newly diagnosed with cryptococcal meningitis in Thailand, South Africa, Malawi and Uganda. All the participants were antiretroviral-naive at baseline.

The participants were followed for ten weeks after diagnosis. To establish the factors associated with longer-term outcomes, participants in the South African cohort were monitored for one year.

The study population comprised 501 participants. The median age was 34 years and 52% were men. Three-quarters were already known to be HIV positive when cryptococcal meningitis was diagnosed. Median CD4 cell count was only 23 cells/mm³.

Induction therapy with amphotericin B (0.7-1mg/kg/day) was initiated in 80% of participants and 20% received fluconazole-based treatment (median 1200mg/day). Almost all (97%) of the participants treated with fluconazole were located in Malawi and Uganda.

Mortality rates were high. All-cause mortality was 17% at week two and by week ten 34% of participants had died.

ART was started by 244 of the 410 people who were still in care at week two. HIV therapy was initiated a median of 30 days after starting antifungal treatment.

Baseline factors associated with mortality at week two were older age (p = 0.009), seizures (p = 0.007), altered mental state (p < 0.001), low CD4 cell count (p = 0.05), low haemoglobin (p = 0.02), high white cell count (p < 0.001), high cerebrospinal fluid fungal burden (p < 0.001) and treatment with fluconazole (p = 0.005). After controlling for CD4 cell count and fungal burden, older age (p = 0.02), altered mental state (p < 0.001), high white cell count (p = 0.002) and fluconazole therapy (p = 0.05) remained significant.

Factors independently associated with mortality at week ten were age (p = 0.009), altered mental status (p< 0.001), low body weight (p = 0.004), low haemoglobin (p = 0.02), elevated white blood cell count (p= 0.02), cerebrospinal fluid opening pressure (p = 0.002), fungal burden (p = 0.007) and fluconazole therapy (p = 0.02).

Analysis of longer-term outcomes among participants in South Africa was restricted to the people who received treatment with amphotericin B (263 of 266). There was a 13% mortality rate among these participants at week two. This increased to 30% at week ten and to 41% at the end of follow-up.

Of the patients surviving to week two, 85% started ART a median of 31 days after initiating antifungal treatment. Immune reconstitution inflammatory syndrome (IRIS) developed in 13% (n = 22) of individuals, of whom 18% (n = 4) died. IRIS was associated with fungal burden at day 14 (p = 0.007) but not ART (p = 0.4).

The majority of deaths during the first two weeks of follow-up were attributed to cryptococcal meningitis (85%). Subsequent deaths were mainly due to other HIV-related complications (67%). Neither earlier initiation of ART nor IRIS was associated with an increased risk of death for participants who started HIV therapy.

The authors believe their findings have a number of important clinical implications. “Earlier diagnosis of CM should be possible, resulting in lower fungal loads at presentation and reduced mortality,” they conclude. “Screening for sub-clinical infection with point-of-care antigen tests and pre-emptive antifungal treatment, along with early ART, could prevent a substantial proportion of clinical disease from developing.” The investigators also suggest that increasing access to amphotericin B therapy should be a priority that and “prompt initiation of ART is required to address the substantial proportion of deaths in these patients that are HIV[-] but not CM-related.”